COVID-19 Vaccines Protect Against 2 SARS-CoV-2 Variants
Posted on Feb 19, 2021
Efficacy of mRNA vaccines on SARS-CoV-2 variants (UK and South Africa)
Detection of mutations arising in the genome of the SARS-CoV-2 virus responsible for COVID-19 have led to concerns that new forms of the virus might enable it to evade the protection conferred by recently approved mRNA vaccines. Two strains in particular, B.1.1.7 from England and B.1.351 from South Africa, are driving the unease. B.1.1.7, first reported in September 2020, has been shown to be more transmissible than the previous strain and is spreading globally. The South African mutant was reported in mid-December 2020 by health authorities there as becoming the chief variant, an indication of heightened transmissibility. This strain garnered additional attention because the portion of Novavax’s Phase 3 vaccine trial conducted in South Africa showed noticeably lower efficacy there than in the UK portion.
Increased levels of contagiousness as a feature of mutant strains are perhaps not too surprising, as modifications leading to enhanced transmission would be subject to strong selection. Both variants have mutations within the receptor-binding domain of the virus’ so-called spike protein that it uses to bind angiotensin converting enzyme 2 (ACE2), a receptor on the surface of human cells, as a way to gain entry and begin replication after co-opting host cellular machinery. They share a mutation called N501Y that replaces asparagine, the 501st amino acid in the spike protein, with tyrosine. Studies in cells and animal models have indicated that this change allows tighter binding to ACE2.
Heightened transmissibility creates its own problems by increasing the number of cases and therefore the number of hospitalizations and deaths. However, a larger concern is whether mutations might reduce neutralization of the virus in the vaccinated population primed to repel it based on the particular protein epitopes contained in the vaccines.
Some viruses mutate their proteins to avoid being blocked by antibodies from infecting cells, a process known as antigenic drift. While there have been suggestions from the UK that B.1.1.7 may be deadlier than previous strains, such antibody-escape mutations do not necessarily lead to more severe disease once an infection succeeds, and according to experts the reasons for any increased lethality remains to be confirmed. Overall consensus among health authorities is that the mutations observed thus far are unlikely to allow the virus to completely escape binding by vaccine-induced antibodies. However, more data is obviously needed.
Addressing this need, two manuscripts that used in vitro methods to explore the extent to which these variants might impact the vaccine efficacy calculated during clinical trials have just been released as pre-prints, i.e., prior to peer review. One is from Moderna, the company that produced a highly effective mRNA vaccine, and the other from the lab of famed HIV researcher David Ho at Columbia University.
Researchers from Moderna and the Vaccine Research Center at NIH used in vitro methods to evaluate antibodies from eight people inoculated with the company’s vaccine using retroviruses expressing the spike proteins of either B.1.351 or B.1.1.7. The antibodies were able to neutralize the engineered chimera in both cases, although six-fold higher levels were required for the South African strain (B.1.351) than for the original protein. In a press release, the company scientists said that while they observed a reduction in antibody potency with B.1.351, the level of neutralizing antibodies “remain above levels that are expected to be protective,” and that B.1.1.7 did not impact antibody potency.
The study by Ho’s lab (being reviewed at Nature) used engineered pseudoviruses for in vitro testing of sera from 20 people vaccinated with either of the two mRNA vaccines, Moderna or Pfizer/BioNTech, as well as “convalescent” plasma from 22 persons who had recovered from infection by the actual virus. They found that the spike RBD from the English variant was “modestly more resistant” to either vaccinee sera (~2 fold) or convalescent plasma (~3 fold), while the South African strain was “relatively resistant,” with vaccinee sera six to nine times less effective in neutralizing the RBD pseudovirus. Sera from previously infected persons was 11 to 33 times less potent. Ho’s team separately evaluated each of B.1.351’s nine mutations and found that mutation E484K accounted for much of its ability to escape antibody binding.
While such decreases in potency may sound alarming, there are several reasons vaccine experts have given for why this is not cause for panic. First, the mRNA vaccines in particular generate high antibody titers and thus are in vivo quite likely to protect against infection by the variants. In addition, antibodies are only one aspect of an immune response. Vaccines also trigger the production of memory T cells that have been shown to be particularly effective against SARS-CoV-2 in several previous seroprevalence studies, even when antibody titers have appeared to be somewhat low. Another important point to keep in mind is that even the lowered efficacy against infection seen with non-mRNA vaccines like J&J’s single shot (72% in US trials, 66% worldwide), the vaccine nonetheless provided much higher percent efficacy against severe disease. There was total protection (100%) against hospitalization or death in phase 3 trials.
Overall, while we are fortunate that coronaviruses have only about half the mutation rate of influenza and one-fourth that of HIV, we can expect further mutations, and these can only be reduced by limiting the transmission of the virus itself. While the consensus is that there is no cause for alarm currently, experts agree that over time enough modifications will occur that new vaccines will be needed. Prudently, both Moderna and Pfizer/BioNTech are preparing for this eventuality, with Moderna announcing a phase 1 trial of two booster strategies addressing mutations and Pfizer announcing they are “laying the groundwork to respond quickly if a future variant of SARS-CoV-2 is unresponsive to existing vaccines.”
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